Many disease states are consistently associated with the occurrence of karyotypic change, e.g., a chromosomal translocation. For example, when the gene encoding PML (for "promyelocytes") undergoes a translocation with the retinoic acid receptor-.alpha. (RAR-.alpha.) (i.e., translocation between chromosomes 15 and 17 at the RAR-.alpha. and PML loci), the translocation is manifested as a form of leukemia, acute promyelocytic leukemia (APL).
It is possible, and even likely in many cases, that when translocation occurs, a gene product not normally subject to hormone expression control (e.g., PML) may be placed under the control of a hormone responsive sequence (e.g., RAR-.alpha.). Thus a gene such as PML may fall under the control of a hormone responsive sequence (such as RAR-.alpha.) as a result of a translocation event.
It has recently been discovered that APL can be effectively controlled by treatment with retinoic acid. Unfortunately, since several different receptors (and subtypes thereof) are known which respond to retinoic acid (e.g., RAR-.alpha., RAR-.beta., RAR-.gamma., RXR-.alpha., RXR-.beta., RXR-.gamma.), administration of retinoic acid as a treatment for APL has the potential to cause many undesirable side-reactions for the patient.
There are numerous other disease states which have also been found to be responsive to treatment with hormones and/or hormone-like compounds. For example, Vitamin D-dependent Ricketts is responsive to treatment with Vitamin D, acne is responsive to treatment with retinoic acid, and the like. While available hormone or hormone-like compounds are effective for the treatment of such disease states, there is always the competing concern of undesirable side effects of such hormone treatments.
Accordingly, such disease states can potentially be much more effectively treated by using ligands which are selective for the specific receptor subtype which is involved in the disease state. Indeed, in view of the potential for the use of hormone therapy in the treatment of many disease states, it would be desirable to have the ability to selectively treat subjects with compounds which selectively interact as ligands with the specific receptor subtype involved in the disease state.